Cancer is a disease that seriously jeopardizes the health of human beings. Around the globe, about 6 millions people die of cancer every year, with another 10 millions seriously affected by the disease. According to the estimate of the World Health Organization, in the 21st century, cancer will become the “number one killer” of mankind.
In the past several decades, many ways of treating cancer became available, mainly including surgery, radiotherapy, chemotherapy, hormonotherapy, gene therapy, and immunotherapy, among which surgery, radiotherapy and chemotherapy have become the major means. Chemotherapy refers to treating cancer with chemical medication. It is the most rapidly expanding field in the diagnosis and treatment of cancer. A great number of new medicines aiming at different targets are ready for clinical application, and developments in research in mechanism of drug action and pharmacokinetics have made the clinical administration routes and means more fitting for killing tumor cells while protecting the normal tissues.
At present, pharmaceuticals for chemotherapy mainly includes: compounds that affects the biosynthesis of nucleic acid (e.g., 5-fluorouracil, amethopterin, cytarabine, hydroxyurea); compounds that directly destroys DNA and prevents its reproduction, e.g. alkylating agents (e.g., cisplatin and carboplatin); antineoplastic antibiotics (e.g., daunorubicin, mitomycin C) compounds that interferes with the transcription and prevents the synthesis of RNA (e.g., actinomycin D, adriamycin) and other transcription restraining antibiotics; compounds that affects the synthesis of protein (e.g., catharanthines, podophyllotoxins, asparaginase) hormones (e.g., adrenal cortical hormone, estrogen, androgen, tamoxifen, aminoglutethimide). The property of interfering in the polymerization or depolymerization of microtubulin of many natural medicines is regarded as having antineoplastic activity. Historically, research focused on two classes of antimitotic agents. The first class includes compounds that bind reversibly to tubulin and prevent microtubule assembly (e.g., colchicine, vinblastine, combretastatin). The second class of antimicrotubule agents features molecules that prevent microtubule disassembly (e.g., taxotere, epothilone, discodermolide, eleutherobine).
Despite the utility of taxus and vinca alkaloids in the clinic, there are serious limitations to these therapies. On-target toxicity of these agents is associated with the notion that tubulin polymers play a critical role in the non-mitotic cytoskeletal functions in both proliferating and terminally differentiated cells. Microtubules are also essential for axonal transport in neurons. Peripheral neurotoxicity of Paclitaxel™, Docetaxel™ and Vincristine™ has been extensively studied. Although manageable and reversible for the majority of second-generation anti-mitotic drugs, this severe side effect may preclude repeated courses of therapy. Neuropathy continues to be an issue for novel agents in clinical development, for example dolastatin-10. In addition, drug efflux pumps play a role in tumors developing resistance to the tubulin-binding drugs. For example, vinca alkaloids and taxanes are both substrates for the P-gp efflux pump encoded by the multidrug resistance mdr1 gene, resulting in decreased sensitivity to these compounds in vivo. Due to these limitations of the tubulin-binding antimitotic agents, there is ongoing need to identify new subsets of antimicrotubule agents that yield anti-mitotic effect with better specificity and more predictable pharmacology
One major drawback when treating cancer is to achieve selectivity against this type of cancer cells. Most chemotherapy against these types of cancer comprises: anti-estrogen therapy such as tamoxifene, raloxifene and toremifene that are Selective Estrogen Receptor Modulators (SERM) that block estrogen's action on some tissues or organs and acts like estrogen on others. They are used for both pre- and postmenopausal women and considered as the first-line hormone therapy. In addition, there is also fulvestrant that is a pure estrogen receptor antagonist.
Selective aromatase inhibitors such as letrozole, anastrozole and exemestane, and nonselective aromatase inhibitors such as aminoglutethimide and testolactone are blocking the function of the enzyme aromatase, which is needed to convert pre-estrogen into a biologically active form. These molecules block the conversion of a pre-estrogen compound produced by tissues other than the ovaries into estrogen. They are used also in the first- and the second-line therapy for early stage breast cancer as well as for postmenopausal women. In the third-line therapy are found progesterone-like drugs such as megestrol acetate. These drugs are traditionally used in postmenopausal women after tamoxifen no longer works. Finally, there are the Luteinizing Hormone-Releasing Hormone (LHRH)-like drugs such as goserelin and leuprolide acetate that reduce estrogen production by the ovaries and used in premenauposal women in complement with aromatase inhibitors.
There remains a need to discover and synthesize new potent compounds having selective activity against certain types of cancer cells, there by providing highly selective anti-cancer molecules.
Certain substituted 2-imidazolidones have now been found to be specific for certain types of cancer cells.